Nano-catalytic carbon dot disrupts hypoxia-driven cascade reaction and ameliorates temozolomide-mediated glioblastoma...

Glioblastoma (GBM), the most aggressive WHO grade 4 brain tumor, has a median survival of ~15 months and a five-year survival rate of only 7%. The current surgical and chemotherapeutic approaches remain insufficient for its treatment. A major obstacle in its treatment is the presence of hostile tumor microenvironment (TME), marked by severe hypoxia, elevated H₂O₂ and acidic pH, which promotes resistance to the standard drug, Temozolomide (TMZ). Hypoxia, orchestrated by HIF-1α, stabilizes TMZ in its inactive form, reducing its efficacy. To address this, we developed plant-based carbon dots (ASA@p-CD, ~8 nm) with catalase, peroxidase, glycosidase, and phosphatase-like multienzyme activities that enhance active TMZ conversion by ~1.27 fold. In U-87 MG cells, ASA@p-CD + TMZ treatment increased cytotoxicity by ~2.71 fold while ASA@p-CD alleviated hypoxia, reducing HIF-1α by ~1.5 fold and ROS by ~2.0 fold. Overall, this suppressed hypoxia signalling, impaired DNA repair and enhanced apoptosis, established ASA@p-CD as a TME-responsive, bifunctional nano-catalytic agent which may pave the path for future cancer therapeutics.